Insulin versus oral agents in the management of Cystic Fibrosis Related Diabetes: a case based study

Onady, Gary M.; Langdon, Leora J

doi:10.1186/1472-6823-6-4

Cited by 29 publications

(19 citation statements)

References 20 publications

(16 reference statements)

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“…While CFRD is traditionally believed to be caused by insulinopenia due to pancreatic b cell fibrosis, recent studies have suggested that impaired insulin sensitivity contributes to CFRD and that insulin resistance frequently develops during infections (37,43). Small observational studies of patients with CFRD have demonstrated that metformin is not associated with adverse events such as hypoglycemia or lactic acidosis (37). Furthermore, the efficacy of metformin was comparable to that of insulin, in regard to HbA 1C reduction and weight gain.…”

Section: Discussionmentioning

confidence: 92%

“…The incidence of CFrelated diabetes mellitus (CFRD) has been increasing with the increased lifespan of individuals with CF, currently occurring in approximately 30% of adult patients with CF as per the CF patient registry. While CFRD is traditionally believed to be caused by insulinopenia due to pancreatic b cell fibrosis, recent studies have suggested that impaired insulin sensitivity contributes to CFRD and that insulin resistance frequently develops during infections (37,43). Small observational studies of patients with CFRD have demonstrated that metformin is not associated with adverse events such as hypoglycemia or lactic acidosis (37).…”

Section: Discussionmentioning

confidence: 99%

“…As AICAR (acadesine) is currently only available in intravenous formulation and has only been tested clinically for brief time periods (hours to days) in the setting of acute myocardial ischemia and reperfusion (36), we decided to pursue additional preclinical studies with metformin, one of the most widely prescribed drugs in the world for the treatment of type 2 diabetes mellitus. Unlike other oral diabetes drugs like sulfonylureas, metformin does not have significant hypoglycemic effects on nondiabetic subjects, and it also does not cause significant weight loss in nonobese subjects with CF (37,38). These considerations make metformin a potentially attractive choice for use in patients with CF lung disease.…”

Section: Preclinical Studies To Evaluate the Potential Utility Of Metmentioning

confidence: 99%

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AMPK Agonists Ameliorate Sodium and Fluid Transport and Inflammation in Cystic Fibrosis Airway Epithelial Cells

Myerburg

King²,

Oyster³

et al. 2010

Am J Respir Cell Mol Biol

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The metabolic sensor AMP-activated kinase (AMPK) inhibits both the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) Cl -channel and epithelial Na 1 channel (ENaC), and may inhibit secretion of proinflammatory cytokines in epithelia. Here we have tested in primary polarized CF and non-CF human bronchial epithelial (HBE) cells the effects of AMPK activators, metformin and 5-aminoimidazole-4-carboxamide-1-b-D-riboside (AICAR), on various parameters that contribute to CF lung disease: ENaC-dependent short-circuit currents (I sc ), airway surface liquid (ASL) height, and proinflammatory cytokine secretion. AMPK activation after overnight treatment with either metformin (2-5 mM) or AICAR (1 mM) substantially inhibited ENaC-dependent I sc in both CF and non-CF airway cultures. Live-cell confocal images acquired 60 minutes after apical addition of Texas Red-dextran-containing fluid revealed significantly greater ASL heights after AICAR and metformin treatment relative to controls, suggesting that AMPK-dependent ENaC inhibition slows apical fluid reabsorption. Both metformin and AICAR decreased secretion of various proinflammatory cytokines, both with and without prior LPS stimulation. Finally, prolonged exposure to more physiologically relevant concentrations of metformin (0.03-1 mM) inhibited ENaC currents and decreased proinflammatory cytokine levels in CF HBE cells in a dose-dependent manner. These findings suggest that novel therapies to activate AMPK in the CF airway may be beneficial by blunting excessive sodium and ASL absorption and by reducing excessive airway inflammation, which are major contributors to CF lung disease.Keywords: metformin; cystic fibrosis transmembrane conductance regulator; ENaC; airway surface liquid; inflammationThe serious genetic disease cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) Cl -channel expressed at the apical membrane in a variety of epithelial tissues, including the lung, where CF lung disease causes considerable morbidity and mortality (1). Defective CFTR function prevents airway epithelium from adequately regulating the airway surface liquid (ASL) volume, which has an adverse effect on mucus clearance from the lung. The CF airway invariably becomes colonized by bacteria such as Pseudomonas aeruginosa and develops excessive inflammation, which can cause extensive damage to lung architecture and eventuate in respiratory failure (2). There is growing evidence that a lack of functional CFTR promotes an exaggerated or prolonged inflammatory response to bacterial and other insults, although the underlying pathophysiologic mechanisms are unclear (3-5). Both up-regulation of proinflammatory mediators (e.g., IL-8, IL-6, TNF-a, and GM-CSF) and down-regulation of anti-inflammatory mediators (e.g., IL-10 and inducible nitric oxide synthase) in the CF airway may play an important role in this process (6-8).Excessive activity of the epithelial sodium channel (ENaC) on the luminal airway surface is a key factor involved in th...

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Preclinical Studies To Evaluate the Potential Utility Of Metmentioning

confidence: 99%

See 1 more Smart Citation

AMPK Agonists Ameliorate Sodium and Fluid Transport and Inflammation in Cystic Fibrosis Airway Epithelial Cells

Myerburg

King²,

Oyster³

et al. 2010

Am J Respir Cell Mol Biol

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“…Apesar das poucas evidências clínicas, existem pacientes que são controlados com antidiabéticos orais secretagogos de insulina, como glinidas (repaglinida) (47) e sulfoniluréias (glibenclamida) (48,49), enquanto a relação risco-benefício é ainda incerta para a utilização de agentes sensibilizantes da ação insulínica, como a metformina e as tiazolidinedionas (49). A acarbose, um inibidor da enzima alfa-glicosidase, apesar de reduzir a glicemia pós-prandial, causa diarréia, anorexia e desconforto abdominal, não sendo indicada para pacientes desnutridos (16,41).…”

Section: Diabetes Relacionado à Fibrose Císticaunclassified

O diabetes melito na fibrose cística: uma comorbidade cada vez mais freqüente

Manna

Setian

Rodrigues

2008

Arq Bras Endocrinol Metab

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RESuMOo diabetes melito (dM) é a principal comorbidade relacionada à fibrose cís-tica (Fc) e costuma acontecer após os 15 anos de idade, associando-se ao aumento da morbimortalidade. sua fisiopatologia inclui destruição do tecido exócrino, insuficiência endócrina e aumento da resistência insulínica, determinando inicialmente a alteração da cinética secretora da insulina, até o comprometimento de sua secreção total. A hiperglicemia pós-prandial é a alteração clínica mais precoce e sintomas do dM podem não ser reconhecidos. A investigação anual deve ser realizada por meio da glicemia de jejum ou de glicemias ao acaso e do teste oral de tolerância à glicose (ogtt). são reconhecidas duas categorias de diabetes relacionadas à Fc: o drFc sem hiperglicemia de jejum (HJ) (glicemia de jejum < 126 mg/dl e glicemia de 2 horas ogtt > 200 mg/dl) e drFc com HJ (glicemia de jejum ≥ 126 mg/dl). o tratamento inclui o manejo nutricional especializado e a correção da hiperglicemia. A insulinoterapia é recomendada para a categoria drFc com HJ, não existindo ainda evidências do benefício de drogas secretagogas ou sensibilizantes da ação insulínica. ABStRActCystic Fibrosis-Related Diabetes: A Frequent Co-morbidity. cystic fibrosis-related diabetes (cFrd) is a major co-morbidity generally affecting patients over 15 years old and it is associated with increased morbidity and mortality. the pathophysiology includes exocrine tissue destruction, insulin deficiency and insulin resistance; the carbohydrate metabolism dysfunction begins with an altered kinetic in insulin secretion followed by a progressive insulin deficiency. Postprandial hyperglycemia is the first abnormality seen in cF patients and the classical symptoms of diabetes may not be recognized. the screening strategy proposed is annual random plasma glucose or fasting plasma glucose investigation, as well as the performance the oral glucose tolerance test (ogtt). two categories of diabetes are related to cF: cFrd without fasting hyperglycemia (fasting glucose < 126 mg/ dl and 2h ogtt glucose > 200 mg/dl) and cFrd with fasting hyperglycemia (fasting glucose ≥ 126 mg/dl). nutritional management and hyperglycemia control are the cFrd treatment goals. insulin control is the standard medical therapy for cFrd with fasting hyperglycemia and the benefits of oral insulin secretagogue and sensitizing agents are still controversial.

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“…Orale Antidiabetika werden in der Praxis zwar nicht selten "offlabel" den Patienten rezeptiert, sind aber bisher nicht hinreichend bezüglich Wirksamkeit und Sicherheit bei CFRD untersucht. Einzelne Berichte deuten aber einen möglichen Einsatz bei früh diagnostiziertem CFRD an [16]. Sie können aus diesem Grund nur innerhalb von kontrollierten Studien, die aktuell noch laufen, eingesetzt werden.…”

Section: Introductionunclassified

Mukoviszidose und Diabetes

Ballmann

2010

Diabetologe

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Die Mukoviszidose oder zystische Fibrose (CF) ist die häufigste letale autosomal-rezessive Erkrankung in unseren Breiten. Die Therapiefortschritte verlängern das Überleben (mittleres Überleben 2008 bei 36 Jahren) deutlich. Dies hat aber anderseits zur Folge, dass Komorbiditäten, die sich erst im Verlauf der Erkrankung zeigen, auch zum Tragen kommen. Die häufigste Komorbidität ist der CFRD (CF-assoziierter Diabetes). Ihm wird ein negativer Einfluss auf den klinischen Verlauf der CF zugeschrieben. Die Pathogenese des CFRD unterscheidet sich sowohl vom Typ-1-als auch vom Typ-2-Diabetes. Dies hat sowohl auf die Diagnose als auch auf die Therapie erhebliche Auswirkungen.

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Insulin versus oral agents in the management of Cystic Fibrosis Related Diabetes: a case based study

Cited by 29 publications

References 20 publications

AMPK Agonists Ameliorate Sodium and Fluid Transport and Inflammation in Cystic Fibrosis Airway Epithelial Cells

AMPK Agonists Ameliorate Sodium and Fluid Transport and Inflammation in Cystic Fibrosis Airway Epithelial Cells

O diabetes melito na fibrose cística: uma comorbidade cada vez mais freqüente

Mukoviszidose und Diabetes

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